Pathogenesis and pathophysiology of heart failure with reduced ejection fraction: translation to human studies

• Published in: Heart failure reviews Vol. 24; no. 5; pp. 743 - 758
• Main Authors: Ge, Zijun, Li, Amy, McNamara, James, dos Remedios, Cris, Lal, Sean
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.09.2019; Springer Nature B.V
• Subjects: Adrenergic beta-Antagonists - therapeutic use; Aldosterone; Angiotensin; Angiotensin-Converting Enzyme Inhibitors - therapeutic use; Animals; Cardiology; Cardiotonic Agents - therapeutic use; Clinical trials; Congestive heart failure; Ejection fraction; Genetic Therapy - methods; Heart failure; Heart Failure - drug therapy; Heart Failure - physiopathology; Humans; Medicine; Medicine & Public Health; Mice; Mineralocorticoid Receptor Antagonists - therapeutic use; Molecular Targeted Therapy - methods; Morbidity; Muscle contraction; Renin; Renin-Angiotensin System - drug effects; Sarcoplasmic Reticulum Calcium-Transporting ATPases - genetics; Sarcoplasmic Reticulum Calcium-Transporting ATPases - metabolism; Stroke Volume - drug effects; Ventricle; Ventricular Remodeling - drug effects; Human; Heart failure; Basic sciences; Translational
• ISSN: 1382-4147; 1573-7322
• DOI: 10.1007/s10741-019-09806-0

Heart failure represents the end result of different pathophysiologic processes, which culminate in functional impairment. Regardless of its aetiology, the presentation of heart failure usually involves symptoms of pump failure and congestion, which forms the basis for clinical diagnosis. Pathophysiologic descriptions of heart failure with reduced ejection fraction (HFrEF) are being established. Most commonly, HFrEF is centred on a reactive model where a significant initial insult leads to reduced cardiac output, further triggering a cascade of maladaptive processes. Predisposing factors include myocardial injury of any cause, chronically abnormal loading due to hypertension, valvular disease, or tachyarrhythmias. The pathophysiologic processes behind remodelling in heart failure are complex and reflect systemic neurohormonal activation, peripheral vascular effects and localised changes affecting the cardiac substrate. These abnormalities have been the subject of intense research. Much of the translational successes in HFrEF have come from targeting neurohormonal responses to reduced cardiac output, with blockade of the renin-angiotensin-aldosterone system (RAAS) and beta-adrenergic blockade being particularly fruitful. However, mortality and morbidity associated with heart failure remains high. Although systemic neurohormonal blockade slows disease progression, localised ventricular remodelling still adversely affects contractile function. Novel therapy targeted at improving cardiac contractile mechanics in HFrEF hold the promise of alleviating heart failure at its source, yet so far none has found success. Nevertheless, there are increasing calls for a proximal, ‘cardiocentric’ approach to therapy. In this review, we examine HFrEF therapy aimed at improving cardiac function with a focus on recent trials and emerging targets.